Insulin controls glucose homeostasis by both suppressing hepatic glucose production and stimulating glucose uptake into skeletal muscle and adipose tissue. Impaired insulin action (insulin resistance) contributes to multiple metabolic disorders, including type 2 diabetes, dyslipidemia and cardiovascular diseases. Insulin resistance is not only a hallmark but also a determinant of type 2 diabetes.
Obesity is the primary risk factor for insulin resistance. Multiple factors contribute to insulin resistance. Abnormal lipid accumulation impairs insulin action in skeletal muscle and livers, thereby contributing to systemic insulin resistance in obesity. Obesity is associated with chronic, low grade inflammation that also contributes to insulin resistance. Additionally, adipocytes secrete a variety of polypeptides, collectively called adipokines, which regulate insulin sensitivity. Many proinflammatory cytokines and adipokines have been documented to regulate insulin sensitivity.
Hepatic lipid levels are determined by several physiological processes, including lipogenesis, fatty acid β oxidation, lipid uptake, and very low density lipoprotein (VLDL) secretion. These processes are tightly controlled by metabolites and metabolic hormones, and aberrant regulation results in hepatic steatosis, leading to nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), cirrhosis, and liver failure.
The liver is the key organ for the maintenance of lipid homeostasis. During the fed state, glucose is taken up by hepatocytes and converted to fatty acids and triacylglycerols that are exported via VLDL to extrahepatic tissues. During the fasted state, fatty acids are oxidized to generate ATP and ketone bodies. Ketone bodies, a metabolic fuel, are exported to extrahepatic tissues. Hepatic lipogenesis and fatty acid β oxidation are precisely regulated by metabolic hormones, including insulin and glucagon.
A major therapeutic goal in treating type 2 diabetes is to improve insulin sensitivity. It is extremely important to identify molecules that sensitize insulin action. Moreover, obesity is an important risk factor for NAFLD. Thus, there exists in the art a need for improved methods of treating and preventing metabolic disorders and cardiovascular disease.